The Streptococci make up a medically important genera of microbes known to cause several types of disease in humans, including, for example, otitis media, conjunctivitis, pneumonia, bacteremia, meningitis, sinusitis, pleural empyema and endocarditis, and most particularly meningitis, such as for example infection of cerebrospinal fluid. Since its isolation more than 100 years ago, Streptococcus pneumoniae has been one of the more intensively studied microbes. For example, much of our early understanding that DNA is, in fact, the genetic material was predicated on the work of Griffith and of Avery, Macleod and McCarty using this microbe. Despite the vast amount of research with S. pneumoniae, many questions concerning the virulence of this microbe remain. It is particularly preferred to employ Streptococcal genes and gene products as targets for the development of antibiotics.
The frequency of Streptococcus pneumoniae infections has risen dramatically in the past 20 years. This has been attributed to the emergence of multiply antibiotic resistant strains and an increasing population of people with weakened immune systems. It is no longer uncommon to isolate Streptococcus pneumoniae strains which are resistant to some or all of the standard antibiotics. This has created a demand for both new anti-microbial agents and diagnostic tests for this organism.
FtsL is a membrane bound protein involved in bacterial cell division. ftsL is essential for cell growth and division. An ftsL null mutation results in inhibition of cell division, the formation of long, non-septate filaments, and ultimately cessation of growth and lysis (Gunman, L-M., Barondess, J. J., and Beckwith, J. (1992) J. Bacteriol 174: 7716-7728).
In Escherichia coli the ftsL gene is located immediately upstream of ftsI which codes for Penicillin-binding protein 3, a membrane protein specifically required during septation (Ishino, F., & Matsuhashi, M. (1981) Biochem. Biophys. Res. Commun. 101: 905-911). FtsL is also a cytoplasmic membrane protein with a cytoplasmic N-terminus, a membrane-spanning segment, and a periplasmic carboxy terminus.
Although there are many examples of cell division proteins in E.coli their precise functions are mostly unknown. However it is likely that membrane proteins involved in cell division will have a major role in the regulation of cell division and in septum initiation.
FtsL homologues have been reported in Haemophilus influenzae (Fleischmann, R. et al (1995) Science 269 : 496-512) and Bacillus subtilis (Daniel, R. A., Williams, A. M., Errington, J. (1995) Genbank Accession Z68230).
Clearly, there is a need for factors, such as the novel compounds of the invention, that have a present benefit of being useful to screen compounds for antibiotic activity. Such factors are also useful to determine their role in pathogenesis of infection, dysfunction and disease. There is also a need for identification and characterization of such factors and their antagonists and agonists which can play a role in preventing, ameliorating or correcting infections, dysfunctions or diseases.
The polypeptides of the invention have amino acid sequence homology to a known Bacillus subtilis ftsl protein.